1. Field of the Invention
The present invention concerns the field of cancer therapy. Specifically, the invention concerns methods for treating malignant tumors by administration of attenuated Mycobacterial compositions.
2. Description of Related Art
A long sought goal in cancer therapy has been the development of safe and effective immunotherapeutic agents that can stimulation a patient's immune system to attack cancer cells. A variety of approaches have been tested in this regard with little success. For example, compositions of inactivated cancer cells have been tested as potential cancer vaccines (U.S. Pat. Nos. 6,168,787; 5,882,654 and 5,840,317). Another method for immunotherapy that has been extensively evaluated is the administration of attenuated bacterial pathogens. In particular a number of studies have evaluated the administration of attenuated Mycobacteria for cancer immunotherapy. Mycobacteria are the causative agents of infectious diseases such tuberculosis and even attenuated strains are known to illicit a strong humoral and cell mediated immune response. In particular, a number of studies have evaluated the immunotherapeutic potential of various sub-strains of attenuated bacille Calmette and Guerin (BCG) Mycobacterium bovis (Grange et al., 1983). Unfortunately, immunotherapies with such attenuated bacteria have only been effective in certain very specific cases.
It has been previously demonstrated that intratumoral injection of live BCG can mediate tumor regression of intradermal metastases (Morton et al., 1970; Pardridge et al., 1979). Studies comparing this technique to administration of BCG to non-tumor tissue by standard tine technique or heat perfusion indicated that intratumoral administration was the superior treatment (Morton et al., 1976). However, live BCG has also been installed intravesically for the treatment and prevention of recurrence for some types of bladder cancer. In this case anywhere from 1 to 8×108 colony forming units are administered into the bladder per dosage (Witjes et al., 1993; Lamm et al., 1995). However, both of these treatment methods can potentially result in systemic introduction of bacteria. Because cancer therapies are often used in conjunction with surgical approaches such as full or partial tumor resection, local administration of BCG typically can not immediately follow surgical resections.
Despite the efficacy of Mycobacterial immunotherapy in these certain specific cases wherein the bacteria is administered directly to the tumor little efficacy has been demonstrated when such compositions are administered to sites other then the tumor itself. Since it is preferable, when possible, to surgically remove cancer tissue it would be a highly beneficial to develop a method of delivering Mycobacterial immunotherapy compositions to non-tumor tissue as a post surgical adjuvant to prevent recurrence. However, even using a variety of BCG sub-strains and treatment schedules, Mycobacterial immunotherapy at such sites has failed to show significant protective or anticancer efficacy (Agarwala et al., 2004; Czarnetzki et al., 1993). Additionally, a large randomized trial of BCG in combination with either surgery or chemotherapy failed to show any significant disease free or overall survival benefit attributable to the immunotherapy (Veronesi et al., 1982). Interestingly, these trials each used a very superficial method for administering the attenuated bacteria. For example, Veronesi et al., (1982) delivered BCG via HEAT gun needles. Other groups have used similar techniques such as tine template administration or needle scarification, and have also failed to demonstrate statistically significant protection from tumors such as malignant melanoma (Silver et al., 1983). Thus, to date, there has not been described a clinically effective method of administering Mycobacterial immunotherapy to non-tumor tissue for cancer therapy.